6alpha-chloro-17alpha-hydroxyprogesterone and intermediates obtained in the production thereof



3,322,796 6d-CHLOR0-170t-HYDROXYPROGESTERONE AND INTEEDHATES OBTAlINED IN THE PRODUC- HON THEREOF Howard .l'. Ringold, Enrique Batres, George Rosenlcranz, Octavio Mancera, and Albert Bowers, all of Mexico (Jity, Mexico, assignors, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed Oct. 31, 1958, Ser. No. 779,916 (llairns priority, application Mexico, Nov. 4, 1957, 49,286; Nov. 27, 1957, 49,487; Feb. 25, 1958, 50,220; lane 25, 11958, 51,373

27 Claims. (Cl. 260397.4)

The present invention relates threne derivatives and to thereof.

More particularly the present invention relates to the novel 6a-chloro progesterone, 6ot-chloro-17u-hydroxyprogesterone and its esters of hydrocarbon carboxylic acids of less than 12 carbon atoms, the 21-fluoro derivatives of these compounds, and the l-dehydro derivatives of the aforementioned compounds. The 6ot-chloro compounds as above set forth are potent progestational agents, when administered hoth by the oral route or by injection, being more potent than other corresponding 6-halo derivatives as for example the 6-fluoro compounds. The present invention also relates to the corresponding 6fl-chloro derivatives which are useful intermediates for the production of the aforementioned 6u-chloro compounds.

In accordance With the present invention we discovered that treatment of 3-alkoxy-A -pregnadiene with hypochlorous acid or an agent capable of producing this acid afio'rded directly the 6fi-chloro-A -pregnen-3-one derivative which upon treatment with a strong mineral acid under anhydrous conditions led to the a-chloro compound. Treatment of the last compounds with selenium dioxide under the conditions known in the art gave the corresponding A -dehydro derivatives. Treatment of the 65 or 6ot-chloro-A -pregnen-3-one compounds with an alkyl ester of orthoformic acid led to the formation of novel 3-alkoxy-6-chloro-A -pregnadiene derivatives; the last compounds also exhibit progestational activity of long duration. The same novel compounds of the present invention can also be made by reacting the corresponding 504,61 oxido-3-ethyleneketal compounds with hydrogen chloride, preferably under anhydrous conditions, as disclosed in US. patent application Ser. No. 670,336, filed July 8, 1957, now Patent No. 2,912,520.

The novel compounds of the present invention are illustrated by the following formulas:

to cyclopentanophenana process for the production CHrX Y/\ J or) CHzX 3,322,796 Patented May 30, 1967 CHzX it, Q

In the above formulas Y represents an additional double bond between C1 and represents hydrogen or fluorine atom, R represents a lower alkyl group of less than 6 carbon atoms such as for example methyl, ethyl and propyl and R represents a hydrogen or an acyl group derived from a hydrocarbon carboxylic acid of less than 12 carbon atoms, saturated or unsaturated, straight chain or branched chain aliphatic, cyclic and cyclic-aliphatic Which can be further substituted as for example With chlorine or methoxy. Typical examples of such an acyl group are acetate, propionate, enanthate, trimethylacetate, hernisuccinate, cyclopentylpropionate, benzoate, phenoxypropionate and ,B-chloropropionate.

The novel process of the present invention is illustrated in the following equation:

l R orthoselenium I dioxide 5: Orthoformate formate r j I 0-2 or a saturated linkage, X

G In the above equation R represents the same group as above set forth.

In practicing the novel process as above set forth, A -3-keto steroids, more specifically in the pregnene series, it being further understood that the side chain of the latter compounds be characteristic of progesterone, 17u-hydroxyprogesterone or the corresponding 21-fiuoro (disclosed in US. patent application Ser. No. 712,299, filed J an. 31, 1958, now abandoned) compounds or their esters as above set forth and further that such compounds may also be characterized by having the cortical side chain as for example compound S, cortisone or 9u-halo hydrocortisone or esters or diesters thereof, were treated at room temperature preferably for several hours with a lower alkyl orthoformate such as for example methyl, ethyl or propyl orthoformate in an organic solvent as for example dioxane and in presence of an acid catalyst such as p-toluenesulfonic acid. At the end of the reaction period the resulting 3-alkyloxy-A -pregnadiene was precipitated by diluting the reaction mixture with water, containing preferably small amounts of a tertiary amine, such as pyridine, isolated and purified. Treatment of the last compounds with hypochlorous acid or with a reagent capable of liberating the said acid such as for example alkali metal salts of hypochlorous acid or N-chloro amide or imidd gave directly the 6/3-chloro-A -3-keto compound. Thus for example the 3-alkyloxy-A -pregnadiene compounds dissolved in an organic ketone solvent as for example acetone were treated with N-chlorosuccinimide in presence of sodium acetate, acetic acid and water, preferably at temperatures around C. and for periods of up to several hours. The resulting 6fi-chloro-A -3-keto compounds were precipitated by addition of water, isolated and purified. Treatment of the last compounds dissolved in an organic acid as for example acetic acid or propionic acid, with an anhydrous inorganic acid, preferably dry hydrogen chloride for several hours and at temperatures preferably between to C., followed by isolation and purification gave the 6a-chloro-A -3-ketone derivative. The introduction of an additional double bond between C-1 and C-2 was preferably accomplished by oxidation with selenium dioxide in t-butanol by the known methods. The 6-chloro-3-alkoxy-A -pregnadiene derivatives were prepared by reacting the 6B or 6 t-chloro-A -3-keto compound with a lower alkyl orthoformate under the conditions above set forth.

It may be noted that the process of the present invention may be applied to pregnane compounds having free or esterified hydroxyl groups as above set forth and that the final compounds may be conventionally saponified and the free compounds reesterified in a conventional way.

The following specific examples serve to illustrate but are not intended to limit the present invention.

Example I A solution of 5 g. of progesterone in 35 cc. of anhydrous dioxane was treated with 5 cc. of ethyl orthoformate and '150 mg. of p-toluenesulfonic acid and the mixture was stirred for minutes; 12 cc. of pyridine and 500 cc. of water were slowly added to the stirred solution, with cooling, whereupon an oil separated which crystallized after cooling for 2 hours. The product was extracted with ether, the extract was washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. Recrystallization of the residue from methanol yielded the 3-ethylenol ether of progesterone: M.P. 100-150 C., [ab -36 (chloroform); A max. 24042 Ill 1., log E 4.33.

A mixture of 5 g. of the above enol-ether, 2 g. of anhydrous sodium acetate, 100 cc. of acetone and 20 cc. of water was cooled to 05 C. and treated with 3.9 g. of N-chlorosuccinimide and 2 cc. of glacial acetic acid and the mixture was stirred for 30 minutes at 05 C. It was then diluted with 250 cc. of water and kept overnight in the refrigerator. The precipitate was collected, washed with water, dried under vacuum and recrystallized from acetone, thus producing 6e-chloroprogesterone, M.P. 185-- 187 C.

A slow stream of dry hydrogen chloride was introduced for 1 hour into a suspension of 3 g. of 6fl-chloroprogesterone in 50 cc. of glacial acetic acid, while the temperature of the mixture was kept between 10 and 15 C.; the mixture was then poured into water and the precipitate was collected by filtration, washed with water, dried and recrystallized from ether, thus furnishing 6tx-chloroprogesterone, M.P. 132 C., [0:] +l30 (chloroform), max. 236-38 m log E 4.19.

Example [I A suspension of 5 g. of l7-acetoxyprogesterone in 50 cc. of anhydrous dioxane was mixed with 5 cc. of ethyl orthoformate and mg. of p-toluenesulfonic acid and the mixture was stirred for one and a half hours. The cooled mixture was then treated with 4 cc. of pyridine and 100 cc. of water under stirring and the precipitate formed was collected, washed with water to neutral, dried at room temperature and recrystallized from methanol-water. There was thus obtained 3-ethoxy-l7a-acetoxy-A -pregnadien-ZO-one, M.P. 162 C.; [ab -l34 (CHCl max. 240-42 m log E 4.33.

A mixture of 5 g. of the above enol-ether, 2 g. of anhydrous sodium acetate, 100 cc. of acetone and 32 cc. of water was cooled to 05 C. and then treated with 3.9 g. of N-chlorosuccinimide and 2 cc. of glacial acetic acid. The mixture was stirred for 30 minutes at a temperature of 0-5 C., diluted with 300 cc. of water and kept overnight in the refrigerator. The precipitate formed was collected, washed with water, dried in vacuum and recrystallized from acetone. There was thus obtained 6fl-chloro- 17a-acetoxyprogesterone, M.P. 220-222 C. (dec.); [m1 +1l (chloroform); 7\ max. 240 m 10g E 4.20.

A slow stream of dry hydrogen chloride was introduced into a suspension of 3 g. of the above compound in 50 cc. of glacial acetic acid, while the temperature was maintained below 10 C. After one hour, the mixture was poured into 100 cc. of water containing 20 g. of potassium acetate and cooled. The precipitate was collected by filtration, washed with water, dried and recrystallized from acetonehexane, thus yielding 6a-ch1oro-17a acetoxyprogesterone, M.P. ISO-181 C. (dec.); [0:1 +37 (chloroform); A max. 236 m log E 4.20.

Example III When in the method of the previous examples the ethyl orthoformate was substituted by the propyl triester of othoformic acid, there was obtained as an intermediate 3-propoxy-17a-acetoxy-A -pregnadien-20-one.

In the step of introduction of the chlorine atom at C6,B of this enol-ether, the N-chlorosuccinimide was substituted by N-chloroacetamide. There was thus obtained 6fl-chloro-17or-acetoxyprogesterone identical to the one obtained in accordance with the method of the previous example.

Example IV In other experiment, instead of starting from 17a-acetoxyprogesterone, there was used the caproate of 17ahydroxyprogesterone. Following the procedures described in the previous examples, there was obtained the corresponding intermediate enolether, 6B-chloro-l7a-hydroxyprogesterone caproate and finally the l7-caproate of 6achloro-l7a-hydroxyprogesterone.

Example V A mixture of 2 g. of 6a-chloroprogesterone, 100 cc. of t-butanol, 0.8 g. of freshly sublimed selenium dioxide and 0.5 cc. of pyridine was refined under an atmosphere of nitrogen for 56 hours; the mixture was cooled, filtered through celite, the filter cake was washed with hot tbutanol, and the combined washings and filtrates were evaporated to dryness under reduced pressure. The residue was dissolved in acetone, treated with decolorizing carbon, the solution was dried over anhydrous sodium sulfate and evaporated to dryness. Purification of the residue afforded 6a-chloro-A -pregnadien-3,20-dione.

Example VI By dehydrogenation of 6a-chloro-l7a-hydroxyprogesterone l7-acetate, in accordance with Example V, there was obtained 6a-chloro-A -pregnadien-l7a-ol-3,20-dione 17-acetate.

Example VII By the same method, 6a-chloro-17a-hydroxyprogesterone l7-caproate was converted into 6a-chloro-A -pregnadien-l7a-ol-3,20-dione 17-caproate.

Example VIII 2.0 g. of 6a-chloroprogesterone was dissolved in 14 cc. of anhydrous dioxane; 2 cc. of ethyl orthoformate and 60 mg. of p-toluenesulfonic acid monohydrate were added and the solution was stirred at room temperature for 30 minutes; 200 cc. of water, containing 5 cc. of pyridine was added, the mixture was cooled and extracted with ether. The etherate extract was washed with water, dried over anhydrous sodium sulfate and taken to dryness.

Purification of the crude residue by crystallization afforded 6-chloro-3-ethoxy-A -pregnadien-20-one.

Example IX By the same method there were produced the 17-acetate and caproate of 6-chloro-3-ethoxy-A -pregnadien-17a-ol- 20-one.

Example X Substituting ethyl orthoformate for propyl orthoformate there were produced the corresponding 3-propyl enol ether derivatives of -chloroprogesterone, 6-chloro-17aacetoxyprogesterone and 6-chloro-l7a-propionoxyprogesterone.

Example XI Substituting in Example VIII 6a-Chl0IOprOgeSt6r0ne for 6,8-chloro progesterone there was produced 6-chloro-3- ethoxy-A -pregnadien-20-one identical to that described in the said example. Substituting 6a-chloro-17a-acetoxyprogesterone for 6,8-chloro-17a-acetoxyprogesterone there was produced the same 3-ethyl enol ether as described in Example IX.

Example XII A cooled solution of 5 g. of 3,20-bis-ethylenedioxy-M- pregnene of MP. 180183 C. in 100 cc. of chloroform was mixed with an ether solution of monoperphthalic acid containing 1.2 molar equivalents of the peracid and the mixture was kept at a temperature between and C. for 24 hours in the dark. The reaction mixture was diluted with water and the organic layer was washed with aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Chromatographic purification afforded 3,20-bisethylenedioxy-5 a,6a-oxido-pregnane.

2 g. of the above epoxido-ketal was suspended in 50 cc. of glacial acetic acid and a slow stream of dry hydrogen chloride was introduced into the mixture. The reaction product was worked up following the method described in the previous example. There was thus obtained 6a-chloroprogesterone, identical with the final compound of Example I.

Example XIII A mixture of 5 g. of the 17-caproate of 17a-hydroxyprogesterone, 100 cc. of anhydrous benzene, 40 cc. of ethylene glycol and 600 mg. of p-toluenesulfonic acid was refluxed for 8 hours with the use of an adapter for the continuous removal of the water formed during the reaction. Saturated aqueous sodium bicarbonate solution was added to the cooled mixture and the organic layer was sodium sulfate and evaporated to dryness under reduced pressure. Crystallization of the residue from acetonehexane aiforded the caproate of 3-ethylenedioxy-A -pregnen-17a-ol-20-one.

A cooled solution of 5 g. of the above ketal in cc. of chloroform was mixed with an ether solution of permonophthalic acid containing 1.2 molar equivalents of reagent and the mixture was kept for 16 hours in the dark at a temperature of 0-5 C. It was then diluted with water and the organic layer was separated and washed with water to neutral, dried over anhydrous sodium sul fate and evaporated to dryness. Chromatographic purification of the residue yielded the caproate of 3-ethylenedioxy-5a,6a-oxido-pregnan-l7a-ol-20-one.

Treatment of 3 g. of the above epoxido-ketal in glacial acetic acid with dry hydrogen chloride, such as has been described for this reaction in Example II, produced the caproate of 6a-chloro-l7a-hydroxyprogesterone.

Example XIV When in the method of the previous example the ethylene glycol was substituted by propylene glycol, there was obtained as an intermediate the caproate of 3-propylenedioxy-A pregnen-17a-ol-20-one which was then oxidized with permonophthalic acid to form the caproate of 3 propylenedioxy 5a,6a oxido-pregnan-17a-ol-20-one. Further reaction of the latter with dry hydrogen chloride afforded the same final compound as that obtained in the previous example.

Example XV A mixture of 4 g. of 2l-fluoro-17a-acetoxyprogesterone, 28 cc. of anhydrous dioxane and mg. of p-toluenesulfonic acid monohydrate was stirred for 30 minutes and then mixed under stirring and cooling with 10 cc. of pyridine and 400 cc. of water; the reaction product was extracted with ether and the extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue crystallized from methanolwater to furnish 21 fluoro 17a acetoxy-3-ethoxy-A pregnadien-ZQ-one.

3 g. of the above compound was dissolved in 90 cc. of acetone, cooled to 0 C. and treated with 1.6 g. of anhydrous sodium acetate and 3 g. of N-chlorosuccinimide and finally with 1.5 cc. of glacial acetic acid; the mixture was stirred at a temperature of 0-5 C. for 3 hours, mixed with 500 cc. of ice water and kept overnight at 0 C.; the precipitate was filtered, washed with water, dried and recrystallized from a mixture of ether and acetone containing a few drops of pyridine. There was thus obtained 6fl-chloro-2l-fluoro-l7a-acetoxyprogesterone, which was converted into the 6a-isomer through an adequate acid treatment, such as the reaction with dry hydrogen chloride in glacial acetic acid solution.

Example XVI other ester; thus the l7-caproate of 2l-flu0ro-l7m-hydroxyprogesterone was treated with ethyl orthoformate to produce 2l-fluoro-l7a-capronoxy-3-ethoxy-A -pregnadien-20-one and the latter was converted, by reaction with N chlqrosuccinimide, into 6 8 chloro 21 fluoro ccapronoxyprogesterone, Whose steric configuration at C-6 was inverted by the treatment with dry hydrogen chloride in glacial acetic acid; the l7-cyclopentylpropionate of 21-fiuoro-17a-hydroxyprogesterone was converted by reaction with the tripropyl ester of orthoformic acid into 21 fluoro 17a cyclopentylpropionoxy 3 propoxy- A -pregnadien-20-one, which was treated with N-chlorosuccinimide and then with dry hydrogen chloride to give 6,8 chloro 21 fluoro 17a cyclopentylpropionoxyprogesterone and then 6a-chloro-2l-fluoro-17a-cyclopentylpropionoxyprogesterone.

Example XVII A suspension of 1.8 g. of the 21-acetate of cortisone in 2 cc. of ethyl orthoformate, 0.1 cc. of anhydrous ethanol and 10 cc. of anhydrous dioxane was mixed with 0.5 cc. of dioxane containing 0.025 cc. of concentrated sulfuric acid and the mixture was vigorously stirred for 5 minutes when an homogeneous solution was obtained; it was kept for 20 minutes at 25 C. and then 1 cc. of pyridine was added and the solution was evaporated to dryness. The syrupy residue crystallized upon the addition of 5 cc. of methanol containing a few drops of water and recrystallization from methanol containing a little pyridine afforded the pure 21-acetate of 3-ethoxy-A -pregnadien-17a,21 diol-l 1,20-dione.

A suspension of 500 mg. of this compound in a mixture of 10 cc. of acetone, 2 cc. of water and 200 mg. of sodium acetate was cooled to C. and treated with 190 mg. (1.2 mols) of N-chlorosuccinimide and then with 0.2 cc. of glacial acetic acid. After stirring for 1 hour the mixture was poured into water and the precipitate of the 6(3-chloro-cortisone 2l-acetate formed was collected, washed with water, dried and recrystallized from ether. There was thus obtained 300 mg. of the pure compound, MP. 169- 171 0, [e1 +107 (chloroform); ultraviolet absorption maximum: x max. 236-8 ma, log E 4.13.

Example XVIII A slow stream of dry hydrogen chloride was introduced into a solution of l g. of the 21-acetate of 6fl-chloro-cortisome in 50 cc. of glacial acetic acid for a period of 2 hours, maintaining the temperature below 18 C. After pouring into water the precipitate was collected, washed with water, dried and recrystallized from acetone-hexane, thus giving the 21-acetate of 6a-chloro-cortisone.

Example XIX By the same method as described in Example XVII but substituting for N-chloroacetamide, there was produced the 21-acetate of 6B-chloro-cortisone identical to that described in that example.

Example XX When in the method of Example XVII the ethyl orthoformate was substituted by propyl orthoformate (tripropyl ester of orthoformic acid), there was obtained the corresponding 3-en0l-propy1 ether instead of the enolethyl ether. Treatment of this compound with N-chloroacetamide as described gave 6-,8-chloro cortisone 21- acetate.

Example XXI A mixture of g. of the 21-acetate of 9a-fluoro-hydro cortisone, 35 cc. of anhydrous dioxane, 5 cc. of ethyl orthoformate and 150 mg. of p-toluenesulfonic acid was stirred for 35 minutes and then 5 cc. of pyridine and water were added until complete precipitation of the reaction product. The precipitate was collected by filtration, washed with water, dried and recrystallized from methanol. There was thus obtained the 21-acetate of 9a-fluoro- 3-ethoxy A pregnadien-l1B,17a,21-triol-20-one, M.P. 158-162 C., x max. 240 mp, log E 4.31.

A mixture of 4 g. of the 21-acetate of 9a-fiuoro-3-ethoxy-A -pregnadien-11e,17a,21-trio1-20-one, 2.1 g. of anhydrous sodium acetate and 120 cc. of acetone was cooled to 0 C. and treated with 3.7 g. of N-chlorosuccinimide followed by 2 cc. of glacial acetic acid; the mixture was stirred for 3 hours at a temperature between 0 and 5 C. and then .ice water was added. The mixture was kept overnight .at around 0 C., the precipitate was collected by filtration, washed with water, dried under vacuum and recrystallized from ether-acetone containing a little pyridine. There was thus obtained the 2l-acetate of 6B-Ch101O-9ozfluoro-hydrocortisone, max. 238 m log E 4.17,

[041 +44 (chloroform).

A mixture of 3 g. of the above compound and 120 cc. of acetic acid was mixed with 4 cc. of aqueous concen- By the same method as described in the previous example, the 21-acetate of 9a-chloro-3-ethoxy-A -pregnadien-l1fi,l7a,21-triol-20-one was converted into the 21- .acetate of 6B,9m-dichloro-hydrocortisone and then into that of 6a,9a-dichloro-hydrocortisone.

Example XXIII By the same method as described in Example XXI, the 21-propionate of 9a-fluoro-3-ethoxy-A -pregnadien-11B, 17oc,21-tli0l-20-0116 was converted into the 2l-propionatc of 6fi-chloro-9a-fluoro-hydrccortisone and then into that of 6a-chloro-9a-fiuoro-hydrocortisone.

Example XXIV By the same method as described in Example XXI, the 21-cyclopentylpropionate of 9oc-Ch10l'0 3 propoxy-A pregnadien-l1fl,17a,21-triol-20-one was converted into the 2l-cyclopentylpropionate of 66,9a-dichloro-hydrocortisone and then into that of 6a,9a-dichlorohydrocorti- Example XXV In another experiment, following the method of Example XXI, N-chlorosuccinimide was substituted by N- chloroacetamide, in all these cases 6a-chloro-9a-fiuorohydrocortisone, identical to that described in Example XXI has been produced.

We claim:

1. A compound of the following formula:

wherein Y is selected from the group consisting of a double bond between C1 and C2 and a saturated linkage between C1 and C2, X is selected from the group consisting of hydrogen and fluorine and R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

2. 6a-chloro-A -pregnen-17a-ol-3,20-dione.

3. The hydrocarbon carboxylic ester of less than 12 carbon atoms of 6a-chloro-A -pregnen-1711-01-3,20dione. 4. 6a-chloro-2l-fluoro-M-pregnen-17a-ol-3,ZO-dione.

5. The hydrocarbon carboxylic esters of less than 12 carbon atoms of 6a-chloro-2l-fluoro-A -pregnen-17tx-ol-3, 20-done.

6. 6a-chloro-A -pregnadien-17a-ol-3,20-dione.

7. The hydrocarbon carboxylic ester of less than 12 carbon atoms of 6a-chloro-A -pregnadien-l7a-ol-3,20- dione.

8. 6a-chloro-21-fluoro A pregnadien-17a-ol-3,20- dione.

9. The hydrocarbon carboxylic ester of less than 12 carbon atoms of 6a-chloro-2l-fiuoro-A -pregnadien-lhcl-3,20 dione.

10. 6a chlor0-A -pregnadien-17a-3,20-dione 17-:1cetate.

12. The hydrocarbon carboxylic ester of less than 12 carbon atoms of 6fi-chloro-A -pregnen-17a-ol-3,20-dione. 13. 6/3-chloro-21-fluoro-A -pregnen-17a-ol-3,20-dione.

14. The hydrocarbon carboxylic ester of less than 12 carbon atoms of 6fi-chloro-21-fluoro-A -pregnen-17a-o1- 3,20-dione.

15. 65-chloro-A -pregnadien-17u-ol-3,20-dione.

16. The hydrocarbon carboxylic ester of less than 12 carbon atoms of 6,B-chloro-A pregnadien-17a-ol-3,20- dione.

17. 6B-chloro-2'1-fluoro-A -pregnadien-17a ol 3,20- dione.

18. The hydrocarbon carboxylic ester of less than 12 carbon atoms of 6B-chloro-21-fluoro-A -pregnadiem17aol-3,20-dione.

19. A compound of the following formula:

OHzX

no so;

wherein X is selected from the group consisting of hydrogen and fluorine, R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms and R is lower alkyl.

20. 6-chloro 21-fi-uoro-3-lower alkoXy-A -pregnadiem 17u-ol-20-one.

21. The hydrocarbon carboxylic ester of less than 12 carbon atoms of 6-chloro-21-fiuoro-3-lower alkoXy-A pregnadien-l7a-ol-20-one.

22. 6-chloro-3-lower alkoXy-A -pregnadien-17oa-ol-20- one.

23. The hydrocarbon carboxylic ester of less than 12 carbon atoms of 6-chloro-3-lower alkoxy-A -pregnadien- 17a-ol-3,20-one.

24. 6-chloro-3-lower alkoxy-A -pregnadien-17a-ol-20- one 17-acetate.

25. 6-chloro-17a-acetoxyprogesterone.

26. 6u-chloro-17oc-acetoxyprogesterone.

27. 6,8-chloro-17a-acetoxyprogesterone.

References Cited UNITED STATES PATENTS 2,332,815 10/1943 Ruzicka 2603973 2,818,408 12/1957 Campbell et al 260239.5 2,835,667 5/1958 Ercoli et al 26023955 2,838,528 6/1958 Campbell et a1 260-397.3 2,838,531 6/1958 Ba-bcock et al. 260397.4 2,870,174 1/1959 Djerassi 260397.4 2,883,404 4/1959 Gash et al 260397.47

OTHER REFERENCES Tannhauser et al.: J. Am. Chem. Soc., vol. 78 (June 5, 1956), pages 2658 and 2659.

ELBERT L. ROBERTS, Primal Examiner.

L. H. GASTON, Examiner.

T. I. MORGAN, Assistant Examiner.

um'mu 511x112: rAi'mu' UI'I'ILL CERTIFICATE OF CORRECTION Patent No 3 ,322 ,796 May 30 1967 Howard J. Ringold et a1 It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2 lines 14 to 24, the left-hand formula should appear as shown below instead of as in the patent:

CIIH X C=0 column 3 line 66 for "150 read 105 column 4 line 71 for "refined" read refluxed column 10, line 10, for "3 ,20" read 20 Signed and sealed this 3rd day of September 1968.

(SEAL) Attest:

EDWARD M. Fletcher, Jr.

EDWARD J. BRENNER Attesting Officer Commissioner of Patents 

1. A COMPOUND OF THE FOLLOWING FORMULA: 